7V0P

Cryo-EM structure of SINV/EEEV in complex with Fab fragment of a potently neutralizing human antibody IgG-106

7V0P の概要

• エントリーDOI: 10.2210/pdb7v0p/pdb
• EMDBエントリー: 26947
• 分子名称: Spike glycoprotein E1, IgG 106 Fab heavy chain, IgG 106 Fab light chain, ... (4 entities in total)
• 機能のキーワード: cryo-em, single particle, virus neutralization, intra-virion crosslink, virus-immune system complex, virus/immune system
• 由来する生物種: Eastern equine encephalitis virus; 詳細
• タンパク質・核酸の鎖数: 16
• 化学式量合計: 477906.44

構造登録者

Bandyopadhyay, A.,Klose, T.,Kuhn, R.J. (登録日: 2022-05-10, 公開日: 2023-04-05, 最終更新日: 2024-10-16)

主引用文献

Williamson, L.E.,Bandyopadhyay, A.,Bailey, K.,Sirohi, D.,Klose, T.,Julander, J.G.,Kuhn, R.J.,Crowe Jr., J.E.
Structural constraints link differences in neutralization potency of human anti-Eastern equine encephalitis virus monoclonal antibodies.
Proc.Natl.Acad.Sci.USA, 120:e2213690120-e2213690120, 2023

PubMed Abstract: Selection and development of monoclonal antibody (mAb) therapeutics against pathogenic viruses depends on certain functional characteristics. Neutralization potency, or the half-maximal inhibitory concentration (IC) values, is an important characteristic of candidate therapeutic antibodies. Structural insights into the bases of neutralization potency differences between antiviral neutralizing mAbs are lacking. In this report, we present cryo-electron microscopy (EM) reconstructions of three anti-Eastern equine encephalitis virus (EEEV) neutralizing human mAbs targeting overlapping epitopes on the E2 protein, with greater than 20-fold differences in their respective IC values. From our structural and biophysical analyses, we identify several constraints that contribute to the observed differences in the neutralization potencies. Cryo-EM reconstructions of EEEV in complex with these Fab fragments reveal structural constraints that dictate intravirion or intervirion cross-linking of glycoprotein spikes by their IgG counterparts as a mechanism of neutralization. Additionally, we describe critical features for the recognition of EEEV by these mAbs including the epitope-paratope interaction surface, occupancy, and kinetic differences in on-rate for binding to the E2 protein. Each constraint contributes to the extent of EEEV inhibition for blockade of virus entry, fusion, and/or egress. These findings provide structural and biophysical insights into the differences in mechanism and neutralization potencies of these antibodies, which help inform rational design principles for candidate vaccines and therapeutic antibodies for all icosahedral viruses.

PubMed: 36961925
DOI: 10.1073/pnas.2213690120

実験手法

ELECTRON MICROSCOPY (5.2 Å)